Fused heterocyclic compounds and use thereof

1. A compound of Formula (I)

including enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein:

R 1 is hydrogen or alkyl;

R 2 is

(a) thiazolyl optionally substituted with one to three groups T 1 , T 2 , and/or T 3 , where T 1 , T 2 , T 3 are independently H, alkyl, haloalkyl, halo, heteroaryl, C(O) t T 6 , OT 6 or -T 4 NT 7 T 8 ;

(b) phenyl substituted at the para position with T 1 , and optionally further substituted with groups T 2 and T 3 where

T 1 is optionally substituted heteroaryl, cyano, C(O) t T 6 , or S(O) t N(T 9 )T 6 , and

T 2 and T 3 are independently H, heteroaryl, cyano, C(O) t T 6 , S(O) t N(T 9 )T 6 , halo alkyl, or haloalkyl; or

(c) tetrahydroindole, quinol-6-yl, quinazolin-7-yl, cinnolin-6-yl, isoquinol-6-yl, or phthalazin-6-yl, any of which may be optionally substituted with one to three groups T 1 , T 2 and/or T 3 ;

Z is —NR 3 R 4 ;

R 3 is H, alkyl or cycloalkyl;

R 4 is (aryl)alkyl optionally independently substituted with one to three groups T 1a , T 2a , and/or T 3a , where T 1a , T 2a and/or T 3a are independently OT 6 , S(O) t T 6 , or S(O) t N(T 9 )T 6 ;

or R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form piperidyl, piperazinyl, or morpholinyl, any of which may be optionally independently substituted with one to three groups T 1a , T 2a , and/or T 3a where T 1a , T 2a and/or T 3a are independently H, hydroxy, oxo, or —C(O) t T 6 ;

R 5 is

(a) hydrogen or cyano;

(b) alkyl, alkenyl, (cycloalkyl)alkyl, (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally independently substituted one to three groups T 1b , T 2b , and/or T 3b wherein T 1b , T 2b and/or T 3b are independently H, cyano, —OT 6 , or —S(O) t T 6 ; or

(c) —C(O)R 6 , —C(O)OR 6 , —C(O)—C(O)OR 6 , or —SO 2 R 6a ;

R 6 is H, alkyl, alkenyl, —NR 3b R 4b , heterocyclo, (heterocyclo)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl or (NR 3b R 4b )alkyl, any of which may be optionally independently substituted one to three groups T 1b , T 2b and/or T 3b where T 1b , T 2b and/or T 3b are independently H, alkyl, —C(O) t H, —C(O) t T 6 , —OC(O)T 6 , —OH, —OT 6 , or —S(O) t T 6 ;

R 6a is H, alkyl, alkenyl, —NR 3b R 4b , heterocyclo, (heterocyclo)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, or (NR 3b R 4b )alkyl, any of which may be optionally independently substituted with one to three groups T 1b , T 2b , and/or T 3b where T 1b , T 2b , and/or T 3b are independently H, alkyl, —C(O) t H, —C(O) t T 6 , —OC(O)T 6 , —OH, —OT 6 or —S(O) t T 6 ;

J 1 and J 2 are independently optionally substituted C 1-3 alkylene, provided that J 1 and J 2 are not both greater than C 2 alkylene; and

T 1-1b , T 2-2b , and T 3-3b are each independently

(1) hydrogen or T 6 , where T 6 is

(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;

(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or

(iii) a group (i) or (ii) which is independently substituted by one or more of the following groups (2) to (13) of the definition of T 1-1b , T 2-2b , and T 3-3b ,

(2) —OH or —OT 6 ;

(3) —SH or —ST 6 ;

(4) —C(O) t H, —C(O) t T 6 or —O—C(O)T 6 , wherein t is 1 or 2;

(5) —SO 3 H, —S(O) t T 6 or S(O) t N(T 9 )T 6 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) -T 4 -NT 7 T 8 ;

(10) -T 4 -N(T 9 )-T 5 -NT 7 T 8 ;

(11) -T 4 -N(T 10 )-T 5 -T 6 ;

(12) -T 4 -N(T 10 )-T 5 -H; or

(13) oxo;

T 4 T 5 are each independently

(1) a single bond;

(2) -T 11 -S(O) t -T 12 -;

(3) -T 11 -C(O)-T 12 -;

(4) -T 11 -C(S)-T 12 -;

(5) -T 11 -O-T 12 -;

(6) -T 11 -S-T 12 -;

(7) -T 11 -O—C(O)-T 12 -;

(8) -T 11 -C(O)—O-T 12 -;

(9) -T 11 -C(═NT 9a )-T 12 -; or

(10) -T 11 -C(O)—C(O)-T 12 -;

T 7 ,T 8 ,T 9 ,T 9a , and T 10

(1) are each independently hydrogen or a group provided in the definition of T 6 , or

(2) T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T 1-1b , T 2-2b , and/or T 3-3b ; or

(3) T 7 or T 8 , together with T 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T 1-1b , T 2-2b , and/or T 3-3b ; or

(4) T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ; and

T 11 and T 12 are each independently

(1) a single bond;

(2) alkylene;

(3) alkenylene; or

(4) alkynylene.

2. A compound of claim 1 having formula (IIa) or (IIb)

including enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein:

R 2 is

W is O or S;

X 1 is NHT 8 or OT 6 ;

X 2 and X 2a are independently hydrogen, halo, OT 6 , alkyl, or haloalkyl;

X 3 is optionally substituted heteroaryl cyano, C(O) t T 6 , or S(O) t NT 7 T 8 ;

X 4a is alkyl, haloalkyl, NHT 8 , or OT 6 ;

X 4 , X 5 , X 6 and X 7 are independently chosen from hydrogen, T 6 , OT 6 , or NT 7 T 8 ; and/or X 4 and X 5 may be taken together to be a carbonyl group; and/or X 6 and X 7 may be taken together to be a carbonyl group; and

X 8 and X 9 are independently hydrogen, T 6 , OT 6 , or NT 7 T 8 .

3. A compound of claim 1 having formula (IIIa), (IIIb) or (IIIc)

including enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein:

Ris

W is O or S;

X 1 is NHT 8 or OT 6 ;

X 2 and X 2a are independently hydrogen, halo, OT 6 , alkyl, or haloalkyl;

X 3 is optionally substituted heteroaryl cyano, C(O) t T 6 , or S(O) t NT 7 T 8 ;

X 4a is alkyl, haloalkyl, NHT 8 , or OT 6 ;

X 4 , X 5 , X 6 and X 7 are independently hydrogen, T 6 , OT 6 or NT 7 T 8 ; or X 4 and X 5 may be taken together to be a carbonyl group; or X 6 and X 7 may be taken together to be a carbonyl group; and

X 8 , X 9 , X 10 and X 11 are independently hydrogen, T 6 , OT 6 , or NT 7 T 8 .

4. A compound of claim 1 having formula (IV)

including enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein:

R 2 is

W is O or S;

X 1 is NHT 8 or OT 6 ;

X 2 and X 2a are independently hydrogen, halo, OT 6 , alkyl, or haloalkyl;

X 3 is optionally substituted heteroaryl, cyano, C(O) t T 6 , or S(O) t NT 7 T 8 ;

X 4a is alkyl, haloalkyl, NHT 8 , or OT 6 ;

X 4 , X 5 , X 6 and X 7 are independently hydrogen, T 6 , OT 6 , or NT 7 T 8 ; or X 4 and X 5 may be taken together to be a carbonyl group; or X 6 and X 7 may be taken together to be a carbonyl group.

5. A compound selected from the following:

(i)

′2-[[4-[[[4-(Methylsulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-methylpyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(phenylmethyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;

2-[[6-[(Acetyloxy)acetyl]-4-[[[4-(aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(hydroxyacetyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(ethoxycarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[3,4,5-Trimethoxyphenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(formyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[3,4,5-Trimethoxyphenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(morpholin-4-ylmethylcarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[3,4,5-Trimethoxyphenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(4-methylpiperazin-1-ylmethylcarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-((2-ethoxy) ethoxycarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Methylsulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-((2-ethoxy) ethoxycarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(cyano)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(allyloxycarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(allyloxycarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(phenyloxycarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(methoxycarbonylcarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(dimethylaminomethylcarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(carboxyethylcarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[3,4,5-Trimethoxyphenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(cyclopropylmethyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-((3-(tetrahydrofuranyl)oxycarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(cyclopropylmethyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[3,4,5-Trimethoxyphenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(hydroxyacetyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[3,4,-Dimethoxyphenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(2-propenyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[3,4,5-Trimethoxyphenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(methylsulfonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-methylpyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

6-[[4-morpholinyl-5,6,7,8-tetrahydro-6-(phenylmethyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-quinoline,

1-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(phenylmethyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-[(1-methyl)imidazol-5yl]benzene,

2-[[4-[[[4-(Methylsulfonyl)phenyl]methyl]amino]-5,6,7,8-tetrahydro-6-(ethoxycarbonyl)pyrido[4,3-d]pyrimidin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid methyl amide,

Aminosulfonyl)phenyl]methyl]amino]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[6,7,8,9-tetrahydro-7-(hydroxyacetyl)-4-[[[4-(methylsulfonyl)phenyl]methyl]amino]-5H-pyrimido[4,5-d]azepin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[6,7,8,9-tetrahydro-4-[[[4-(methylsulfonyl)phenyl]methyl]amino]-7-(4-morpholinylacetyl)-5H-pyrimido[4,5-d]azepin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

2-[[7-[(Acetyloxy)acetyl]-6,7,8,9-tetrahydro-4-[[[4-(methylsulfonyl)phenyl]methyl]amino]-5H-pyrimido[4,5-d]azepin-2-yl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-(phenylmethyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-(phenylmethyl)-4-[4-(methylsulfonyl)phenyl]methyl]amino]pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-(phenylmethyl)-4-[4-(aminosulfonyl)phenyl]methyl]amino]pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((3,4-(dimethoxy)phenyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((3,4,5-(trimethoxy)phenyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((4-(methylsulfonyl)phenyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((3-pyridyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimid-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((2-furanyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((3-(cyano)phenyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((4-(cyano)phenyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((2-pyridyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((3-furanyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((3-thenyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((4-pyridyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((2-(cyano)phenyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((2-thiazolyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((4-fluorophenyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((2-thenyl)methyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-(1-(3-pyridyl)ethyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-(1-(2-pyridyl)ethyl)-4-(1-piperazinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-(phenyl)methyl)-4-(3-oxo- 1-piperazinyl)pyndo[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((tetrahydrofuran-3-yl)oxycarbonyl)-4-[4-(aminosulfonyl)phenyl]methyl]amino]pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester,

4-Methyl-2-[[5,6,7,8-tetrahydro-7-((tetrahydrofuran-3-yl)oxycarbonyl)-4-(butyloxy)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester, and

4-Methyl-2-[[5,6,7,8-tetrahydro-7-(dimethylaminosulfonyl)-4-((4-hydroxy)-1-piperidinyl)pyrido[3,4-d]pyrimidin-2-yl]amino]-5-thiazolecarboxylic acid ethyl ester; or

(ii) an enantiomer, diastereomer, or a pharmaceutically acceptable salt of (i), thereof.

6. A compound according to claim 5 , including enantiomers, diastereomers, and pharmaceutically acceptable salts, thereof, selected from the following:

(i)

 or

(ii) an enantiomer, diastereomer, or a pharmaceutically acceptable salt of (i), thereof.